A successful approach to modeling of enzyme substrates has been active analog analysis. This involves identification and use of pharmacophores to search the NCI DIS 3D database. Modeling Studies Validation of two widely used molecular modeling programs has been completed and published. One of these was then selected to build the NCI DIS 3D database. Enzyme Binding It has been shown that flexible ligands, i.e. drugs, are deformed when binding to an active site. Energy audits of this process have established its thermodynamic rationale. Protein Kinase C The pharmacophore in protein kinase C has been identified and used as a target in searches of the NCI 3D database. These searches have produced numerous compounds which are inhibitors in that they compete with phorbol for the active site in PKC. Tyrosine Protein Kinase Substrate binding to this enzyme utilize a tyrosine phosphate and as many as 10 hydrophobic interactions. Such interactions are not well documented and they have therefore been studied. They are weak but ubiquitous and it is thought that they may play a role in the process by which an enzyme recognizes its substrates. Other Enzymes The active analog which has proved successful with protein kinase C is being applied to several other enzymes which are thought to offer chemotherapeutic targets for control of cancer or AIDS. They include HIV protease, HIV integrase and telomerase.